title: Prostate-specific antigen changes as surrogate for overall survival in men with metastatic castration-resistant prostate cancer treated with second-line chemotherapy.
abstract: OBJECTIVE
  Prostate-specific antigen (PSA) kinetics, and more specifically a ≥ 30% decline in PSA within 3 months after initiation of first-line chemotherapy with docetaxel, are associated with improvement in overall survival (OS) in men with metastatic castration-resistant prostate cancer (mCRPC). The objective of this analysis was to evaluate post-treatment PSA kinetics as surrogates for OS in patients receiving second-line chemotherapy.
  
  
  METHODS
  Data from a phase III trial of patients with mCRPC randomly assigned to cabazitaxel plus prednisone (C + P) or mitoxantrone plus prednisone were used. PSA decline (≥ 30% and ≥ 50%), velocity, and rise within the first 3 months of treatment were evaluated as surrogates for OS. The Prentice criteria, proportion of treatment explained (PTE), and meta-analytic approaches were used as measures of surrogacy.
  
  
  RESULTS
  The observed hazard ratio (HR) for death for patients treated with C + P was 0.66 (95% CI, 0.55 to 0.79; P < .001). Furthermore, a ≥ 30% decline in PSA was a statistically significant predictor of OS (HR for death, 0.52; 95% CI, 0.43 to 0.64; P < .001). Adjusting for treatment effect, the HR for a ≥ 30% PSA decline was 0.50 (95% CI, 0.40 to 0.62; P < .001), but treatment remained statistically significant, thus failing the third Prentice criterion. The PTE for a ≥ 30% decline in PSA was 0.34 (95% CI, 0.11 to 0.56), indicating a lack of surrogacy for OS. The values of R(2) were < 1, suggesting that PSA decline was not surrogate for OS.
  
  
  CONCLUSIONS
  Surrogacy for any PSA-based end point could not be demonstrated in this analysis. Thus, the benefits of cabazitaxel in mediating a survival benefit are not fully captured by early PSA changes.
authors.affiliation: Susan Halabi, Andrew J. Armstrong, Ellen Kaplan, Chen-Yen Lin, and Nicole C. Solomon, Duke University, Durham, NC; Oliver Sartor, Tulane University, New Orleans, LA; Johann de Bono, Royal Marsden Hospital, Sutton, United Kingdom; and Eric J. Small, University of California at San Francisco, San Francisco, CA.
authors.forename: Susan
authors.initials: S
authors.lastname: Halabi
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Armstrong
authors.forename: Oliver
authors.initials: O
authors.lastname: Sartor
authors.forename: Johann
authors.initials: J
authors.lastname: de Bono
authors.forename: Ellen
authors.initials: E
authors.lastname: Kaplan
authors.forename: Chen-Yen
authors.initials: CY
authors.lastname: Lin
authors.forename: Nicole C
authors.initials: NC
authors.lastname: Solomon
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Small
mesh_terms: D000368:Aged; D000726:Androgen Antagonists / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000627:therapeutic use; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D008942:Mitoxantrone / Q000627:therapeutic use; D009362:Neoplasm Metastasis; D017430:Prostate-Specific Antigen / Q000097:blood*; D064129:Prostatic Neoplasms, Castration-Resistant / Q000097:blood* / Q000188:drug therapy / Q000401:mortality*; D043823:Taxoids / Q000627:therapeutic use
chemical_list: D000726:Androgen Antagonists; D000970:Antineoplastic Agents; D018931:Antineoplastic Agents, Hormonal; D043823:Taxoids; C552428:cabazitaxel; D008942:Mitoxantrone; D017430:Prostate-Specific Antigen